Stesura Seveso Archivio Italiano di Urologia e Andrologia 2025; 97(3):14279 1 LETTER TO EDITOR KEY WORDS: Prostate cancer; PCA3; PSA; Urinary biomarkers; New biomarkers. Submitted 24 August 2025; Accepted 30 August 2025 Dear Editor, Prostate cancer (PCa) remains one of the most common malignancies among men worldwide, representing a major health- care burden both in terms of morbidity and economic cost (1-5). Over the last two decades, the diagnostic pathway for prostate cancer has been substantially re-evaluated and modelled by the introduction of multiparametric magnetic reso- nance imaging (mpMRI) and targeted biopsies (6-11). While these tools have improved the detection of clinically signifi- cant prostate cancer (csPCa), they have also contributed to a considerable increase in healthcare costs and patient burden. The Urologi Ospedalità Gestione Privata (UROP) scientific association strongly believes that the time has come to shift a substantial part of our research focus towards the development and validation of novel biomarkers that can more effec- tively stratify patients before they reach the stage of repeated imaging and invasive procedures. Over the last decades, the widespread use of prostate-specific antigen (PSA) as a screening tool has historically led to the overdiagnosis and overtreatment of indolent prostate cancers. In an attempt to overcome these limitations, mpMRI has emerged as diagnostic tool. Randomized trials and real-world data have consistently demonstrated its value in guiding biopsies and improving detection of csPCa, while reducing unnecessary procedures in men with low-risk disease (12). However, the use of mpMRI and fusion prostate biopsies comes at a high cost. Imaging is resource-intensive, requires specialized expertise among radiologists, and in many healthcare systems is associated with long waiting lists, multiple hospital visits, and expenses also for patients. Moreover, even in experienced centers, mpMRI interpretation suffers from The need for novel biomarkers in prostate cancer: A UrOP perspective Guglielmo Mantica 1, Stefano Alba 2, Andrea Alfarone 3, Umberto Capitanio 4, Donato Dente 5, Carlo Giulioni 6, Carmelo Morana 7, Serena Maruccia 8, Gabriella Mirabile 9, Gennaro Musi 10, Mauro Ragonese 11, Mauro Silvani 12, Antonio Tufano 13, Angelo Cafarelli 6, Alessandro Calarco 13, Ottavio De Cobelli 10, Ferdinando De Marco 14, Giovanni Ferrari 15, Giuseppe Mario Ludovico 16, Stefano Pecoraro 17, Domenico Tuzzolo 18, Renzo Colombo 4, Nazareno Suardi 19, Rosario Leonardi 20 on behalf of UrOP (Urologi Ospedalità Gestione Privata) 1 Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genoa, Genoa, Italy; 2 Department of Urology, Romolo Hospital, Rocca di Neto (KR), Italy; 3 Department of Urology, Aurelia Hospital, Roma, Italy; 4 Division of Experimental Oncology/Unit of Urology, Urological Research Institute (URI), IRCCS Ospedale San Raffaele, Milan, Italy; 5 Istituto Clinico Città di Brescia, Brescia, Italy; 6 Urology Unit, Villa Igea Private Hospital, Ancona, Italy; 7 Department of Urology, Giovanni XXIII Monastier Hospital, Treviso, Italy; 8 Istituti Clinici Zucchi, Monza, Italy; 9 Center of Minimally-Invasive Urology, Pio XI Clinic, Fondazione Vincenzo Pansadoro, Rome, Italy; 10 Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, Italy; 11 Department of Urology, Policlinico Universitario Fondazione Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS), Roma, Italy; 12 Department of Reconstructive Surgery, Clinica Sedes Sapientiae, Turin, Italy; 13 Urology Unit, San Carlo di Nancy Hospital, Roma, Italy; 14 Department of Urology, Tiberia Hospital, Rome, Italy; 15 Department of Urology, Hesperia Hospital, Modena, Italy; 16 Division of Urology, Ente ecclesiastico Ospedale Generale Regionale "Miulli", Acquaviva delle Fonti (BA), Italy; 17 NEUROMED, Avellino, Italy; 18 Urologi Ospedalità Gestione Privata (UrOP); 19 Department of Urology, Ospedali Civili of Brescia, Brescia, Italy; 20 Division of Urology, School of Medicine, Kore University of Enna, Enna, Italy. DOI: 10.4081/aiua.2025.14279 Archivio Italiano di Urologia e Andrologia 2025; 97(3):14279 G. Mantica, S. Alba, A. Alfarone, et al. 2 inter-reader variability, and not all men with suspicious lesions ultimately harbor significant disease. The subsequent need for targeted and systematic biopsies not only further inflates costs but also exposes patients to complications such as infection, bleeding, and urinary retention (13, 14). In the current era of medicine, this diagnostic pathway, while effec- tive, cannot be considered sustainable in the long run without additional refinement. To address these challenges, in the same line of other cancers such bladder tumors (15), there is an urgent need for bio- markers that can better identify men truly at risk of harboring csPCa before committing them to expensive imaging and invasive testing. These biomarkers should ideally improve risk stratification beyond PSA and clinical parameters, be min- imally invasive (preferably blood, urine, or semen-based), be able to reduce unnecessary mpMRI and biopsies, thereby sparing patients from anxiety, morbidity, and repeated hospital visits. Of course, be cost-effective and easy to be used in clinical practice. Several promising biomarkers and genomic signatures have already been proposed both for diagnosis and targeted ther- apy, including Prostate Health Index (PHI), 4Kscore, PCA3, SelectMDx, ExoDx, and tissue-based genomic panels, but their uptake remains limited, partly due to cost, lack of standardization, and limited integration into clinical guidelines. More importantly, many of these tests have been developed in small or highly selected populations, and their performance in real-world, diverse cohorts is not yet fully established (16-21). While these commercially available tests have demonstrated utility in refining risk assessment and guiding the decision regarding prostate biopsy, their limitations underscore the need for further progress in this field. In this regard, next-gen- eration approaches such as non-coding RNAs, circulating tumor DNA (ctDNA), and analysis of PSA glycosylation patterns are emerging as highly promising tools. These novel biomarkers, currently still under clinical investigation, may allow a better understanding of tumor biology and hold the potential to complement or even surpass existing assays. Recent reviews and translational studies have highlighted their relevance and future role in reshaping the diagnostic landscape of prostate cancer (22-25). From a health economics perspective, every unnecessary mpMRI or biopsy avoided translates into significant cost sav- ings for healthcare systems. Furthermore, reducing the need for repeated hospital visits, possible complications, and invasive tests would have a profound positive impact on patients’ quality of life. Anxiety, physical discomfort, and poten- tial complications associated with biopsies are often underestimated but carry real consequences for men and their fam- ilies. Collaborative, multicenter, prospective validation studies are urgently needed. Importantly, these studies should be designed with cost-effectiveness as a primary endpoint, ensuring that the biomarkers developed are not only clinically useful but also economically viable, both for public and private settings. Another crucial element is accessibility. Biomarkers should be developed ensuring they can be applied across different healthcare settings, including those with limited imaging availability. This would not only optimize resource allocation in high-income countries but also improve equity of access to early and accurate prostate cancer diagnosis worldwide. The UROP hope a future in which the diagnostic pathway for prostate cancer is more personalized, efficient, and sus- tainable. In this vision, biomarkers serve as the first gatekeeper, filtering men who truly require advanced imaging and biopsy from those who can be safely monitored. Such an approach would substantially reduce healthcare costs, mini- mize patient morbidity, and improve overall outcomes. UROP strongly calls upon the international research community, funding bodies, and policymakers to prioritize the development of novel biomarkers for prostate cancer. The current reliance on mpMRI and biopsy-heavy strategies, while valuable, may not be sustainable in the long term. Innovative, accessible, and validated biomarkers represent the next frontier in prostate cancer diagnostics. Investing in this direction is not only a scientific necessity but also a moral imperative, as it will ultimately reduce costs, minimize patient burden, and ensure that care is truly focused on those at greatest risk of clinically significant disease. DECLARATIONS Ethical approval and consent for participate: Not applicable. Consent for publication: Not applicable. Availability of data and material: Not applicable. Competing interests: The authors declare that they have no competing interests. Funding: In case of acceptance, UrOP will pay the APC. Authors' contributions: Guglielmo Mantica and Rosario Leonardi: ideation, paper writing and editing; All Authors: revision and validation. Acknowledgments: Not applicable. Archivio Italiano di Urologia e Andrologia 2025; 97(3):14279 3 Novel biomarkers in prostate cancer REFERENCES 1. MacLennan S, Azevedo N, Duncan E, et al. Mapping European Association of Urology Guideline Practice Across Europe: An Audit of Androgen Deprivation Therapy Use Before Prostate Cancer Surgery in 6598 Cases in 187 Hospitals Across 31 European Countries. Eur Urol. 2023; 83:393-401. 2. Marchioni M, Primiceri G, Castellan P, et al. Conservative management of urinary incontinence following robot-assisted radical prostatecto- my. Minerva Urol Nefrol. 2020; 72:555-562. 3. Bauckneht M, Rebuzzi SE, Ponzano Met, al. Prognostic Value of the BIO-Ra Score in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Radium-223 after the European Medicines Agency Restricted Use: Secondary Investigations of the Multicentric BIO-Ra Study. Cancers (Basel). 2022; 14:1744. 4. Montironi R, Cimadamore A, Lopez-Beltran A, et al. Should pathologists and clinicians continue to consider Grade Group 1 (Gleason score ≤ 6) prostate cancer as a true carcinoma? Let's hear from patient advocates. Arch Ital Urol Androl. 2025; 97:13925. 5. De Nunzio C, Lombardo R, Baldassarri V, et al. Rotterdam mobile phone app including MRI data for the prediction of prostate cancer: A mul- ticenter external validation. Eur J Surg Oncol. 2021; 47:2640-2645. 6. Scarcia M, Andracchio V, Piana A, et al. Learning curve of a multidisciplinary team for magnetic resonance imaging/transperineal ultra- sonography fusion prostate biopsy. Arch Ital Urol Androl. 2025; 97:13933. 7. Pepe P, Pepe L, Fiorentino V, Curduman M, Fraggetta F. Transcutaneous perineal-ultrasound guided prostate biopsy in men with rectal ampu- tation. Arch Ital Urol Androl. 2025 97:14047. 8. Brant A, Campi R, Carrion DM, et al. Findings from an international survey of urology trainee experience with prostate biopsy. BJU Int. 2023; 131:705-711. 9. Mantica G, Pacchetti A, Aimar R, et al. Developing a five-step training model for transperineal prostate biopsies in a naïve residents' group: a prospective observational randomised study of two different techniques. World J Urol. 2019; 37:1845-1850. 10. Cai W, Zhu D, Byanju S, et al. Magnetic resonance spectroscopy imaging in diagnosis of suspicious prostate cancer: A meta-analysis. Medicine (Baltimore). 2019; 98:e14891. 11. Nguyen T, Lightfoot C, May D, et al. Patient Reported Outcomes and Treatment-Associated Complications as a Consideration in Selecting Localized Prostate Cancer Management. Res Rep Urol. 2025; 17:195-210. 12. Klotz L, Chin J, Black PC, et al. Comparison of Multiparametric Magnetic Resonance Imaging-Targeted Biopsy With Systematic Transrectal Ultrasonography Biopsy for Biopsy-Naive Men at Risk for Prostate Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021; 7:534- 542. 13. Mian BM, Feustel PJ, Aziz A, et al. Complications Following Transrectal and Transperineal Prostate Biopsy: Results of the ProBE-PC Randomized Clinical Trial. J Urol. 2024; 211:205-213. 14. Hu JC, Assel M, Allaf ME, et al. Transperineal Versus Transrectal Magnetic Resonance Imaging-targeted and Systematic Prostate Biopsy to Prevent Infectious Complications: The PREVENT Randomized Trial. Eur Urol. 2024; 86:61-68. 15. Malinaric R, Mantica G, Lo Monaco L, et al. The Role of Novel Bladder Cancer Diagnostic and Surveillance Biomarkers-What Should a Urologist Really Know? Int J Environ Res Public Health. 2022; 19:9648. 16. Quistini A, Chierigo F, Fallara G, et al. Androgen Receptor Signalling in Prostate Cancer: Mechanisms of Resistance to Endocrine Therapies. Res Rep Urol. 2025; 17:211-223. 17. Galasso F, Giannella R, Bruni P, et al. PCA3: a new tool to diagnose prostate cancer (PCa) and a guidance in biopsy decisions. Preliminary report of the UrOP study. Arch Ital Urol Androl. 2010; 82:5-9. 18. Boehm BE, York ME, Petrovics G, et al. Biomarkers of Aggressive Prostate Cancer at Diagnosis. Int J Mol Sci. 2023; 24:2185. 19. Wagaskar VG, Sobotka S, Ratnani P, et al. A 4K score/MRI-based nomogram for predicting prostate cancer, clinically significant prostate can- cer, and unfavorable prostate cancer. Cancer Rep (Hoboken). 2021; 4:e1357. 20. Azis A, Islam AA, Rasyid H, et al. Anti-cancer activity of Ajwa Dates extract (Phoenix Dactylifera L.) through analysis of MCL-1 levels, EGFR, and p53 expressions on apoptosis in human prostate cancer cell lines PC3: an in vitro study. Arch Ital Urol Androl. 2025 Aug 4:14027. 21. Plas S, Melchior F, Aigner GP, et al. The impact of urine biomarkers for prostate cancer detection-A systematic state of the art review. Crit Rev Oncol Hematol. 2025; 210:104699. 22. Farha MW, Salami SS. Biomarkers for prostate cancer detection and risk stratification. Ther Adv Urol. 2022 ; 14:17562872221103988. 23. Smelik M, Diaz-Roncero Gonzalez D, An X, et al. Combining Spatial Transcriptomics, Pseudotime, and Machine Learning Enables Discovery of Biomarkers for Prostate Cancer. Cancer Res. 2025; 85:2514-2526. 24. Liu Y, Hatano K, Nonomura N. Liquid Biomarkers in Prostate Cancer Diagnosis: Current Status and Emerging Prospects. World J Mens Health. 2025; 43:8-27. 25. Robinson HS, Lee SS, Barocas DA, Tosoian JJ. Evaluation of blood and urine based biomarkers for detection of clinically-significant prostate cancer. Prostate Cancer Prostatic Dis. 2025; 28:45-55. Archivio Italiano di Urologia e Andrologia 2025; 97(3):14279 G. Mantica, S. Alba, A. Alfarone, et al. 4 Correspondence Guglielmo Mantica - guglielmo.mantica@gmail.com Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genoa, Largo Rosanna Benzi 10, 16136, Genoa, Italy Stefano Alba - stefanoalba78@gmail.com Department of Urology, Romolo Hospital, Rocca di Neto (KR), Italy Andrea Alfarone - alfarone2@hotmail.com Department of Urology, Aurelia Hospital, Roma, Italy Umberto Capitanio - umbertocapitanio@gmail.com Renzo Colombo - colombo.renzo@hsr.it Division of Experimental Oncology/Unit of Urology, Urological Research Institute (URI), IRCCS Ospedale San Raffaele, Milan, Italy Donato Dente - donato.dente@tiscali.it Istituto Clinico Città di Brescia, Brescia, Italy Carlo Giulioni - carlo.giulioni9@gmail.com Angelo Cafarelli - info@angelocafarelli.it Urology Unit, Villa Igea Private Hospital, Ancona, Italy Carmelo Morana - morana.carmelo@gmail.com Department of Urology, Giovanni XXIII - Monastier Hospital, Treviso, Italy Serena Maruccia - serena.maruccia@gmail.com Istituti Clinici Zucchi, Monza, Italy Gabriella Mirabile - gabriella.mirabile@gmail.com Center of Minimally-Invasive Urology, Pio XI Clinic, Fondazione Vincenzo Pansadoro, Rome, Italy Gennaro Musi - gennaro.musi@ieo.it Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, Italy Mauro Ragonese - mauro.ragonese@gmail.com Department of Urology, Policlinico Universitario Fondazione Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS), Roma, Italy Mauro Silvani - dottorsilvani@gmail.com Department of Reconstructive Surgery, Clinica Sedes Sapientiae, Turin, Italy Antonio Tufano - antonio.tufano91@gmail.com Alessandro Calarco - alecalarco@gmail.com Urology Unit, San Carlo di Nancy Hospital, Roma, Italy Ottavio De Cobelli - ottavio.decobelli@ieo.it Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, Italy Ferdinando De Marco - ferdinandodemarco@gmail.com Department of Urology, Tiberia Hospital, Rome, Italy Giovanni Ferrari - gferrari@hesperia.it Department of Urology, Hesperia Hospital, Modena, Italy Giuseppe Mario Ludovico - g.ludovico@miulli.it Division of Urology, Ente ecclesiastico Ospedale Generale Regionale "Miulli", Acquaviva delle Fonti (BA), Italy Stefano Pecoraro - uropec@gmail.com NEUROMED, Avellino, Italy Domenico Tuzzolo - dometuzzolo@alice.it Urologi Ospedalità Gestione Privata (UrOP) Nazareno Suardi - suardi.nazareno@gmail.com Department of Urology, Ospedali Civili of Brescia, Brescia, Italy Rosario Leonardi - rosario.leonardi@unikore.it Division of Urology, School of Medicine, Kore University of Enna, Enna, Italy